Adipose tissue, once considered simply a fuel storage depot, is now recognized as an endocrine tissue that communicates actively with the central nervous system and peripheral tissues, responding to and regulating various neuronal, metabolic and hormonal signals to participate in energy storage, fatty acid metabolism and glucose homeostasis (46, 47). Adipose tissue also plays an important role in the pathogenesis of obesity and its associated diseases such as type 2 diabetes, cardiovascular disease and dyslipidemia (metabolic syndrome).
Regional distribution of adipose tissue is an independent factor for the susceptibility to obesity-associated morbidities. Numerous epidemiological studies have firmly established that central obesity, the accumulation of intraabdominal (omental) fat, as compared with subcutaneous fat, is associated with a higher degree of risk for type 2 diabetes, cardiovascular disease, hypertension, and hyperlipidemia (48, 49). Many investigations have been undertaken to try to understand the reason why abdominal fat is more pathogenic and to study differences between omental and subcutaneous fat. Studies also suggest that these two adipose tissue depots differ in important ways. Omental adipose tissue is more metabolically active with respect to lipolysis and lipogenesis (50, 51). Abdominal fat pads secrete higher pro-inflammatory cytokines such as interleukin 6 (IL-6) (52), plasminogen activator inhibitor (PAI-1) (53), angiotensinogen (54), resistin (55) and exhibit greater apoptosis (56) than that found in subcutaneous fat pads. In contrast, leptin expression is higher in subcutaneous fat tissue than omental fat tissue (57, 58). Omental fat is also less insulin sensitive but more sensitive to beta-adrenergic stimulation (50). It is thought that these depot-specific variations in metabolism may explain features of metabolic syndrome. Because the pathophysiological basis of this syndrome is likely to be complex, several tissues, gene products and pathways may participate in the disease process.
Adipose tissue is composed of a number of different cell types in addition to the adipocytes themselves, such as preadipocytes, endothelial cells, mast cells, pericytes, fibroblasts, macrophages and inflammatory cells (59). These supporting non-adipocyte cells are collectively called stromal-vascular cells (SVC), the majority of which are preadipocytes and endothelial cells. Differing ratios of stromal-vascular cells, innervation, vascularization, anatomical location and metabolic demands may all contribute to the adipose depot-specific differences that are observed.
A variety of bioactive factors that impact energy metabolism, the immune system, angiogenesis and cardiovascular health are secreted by adipose tissue. These factors include leptin, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1 (PAI-1), IL-6, adiponectin/ACRP30/adipoQ, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and resistin (55, 60, 61). Alterations of the levels of cell surface receptors for cytokines could induce changes in insulin action. Adiponectin, a bioactive factor that promotes insulin sensitivity, is decreased in obesity (62, 63). Adipocytes almost exclusively produce leptin and adiponectin (57) as well as large amounts of VEGF (64) and bFGF (65). However, non-adipose stromal-vascular cells produce the majority of PAI-1 (55) and essentially all IL-6 (55), TNF-alpha (Fried, unpublished observations) and resistin (55). Thus, the non-adipocyte cells in adipose tissue significantly contribute to the secretion of bioactive factors that are attributed to this endocrine organ. (74).
In a recent study on obesity, a chronic pathological condition, obesity was associated with increased macrophage infiltration of adipose tissue and production of TNF-alpha, a pro-inflammatory cytokine that causes insulin resistance (75). Endothelial cells of the adipose tissue stromal vasculature play an important role in obesity and obesity-related insulin resistance by secreting monocyte chemoattractant protein-1 (MCP-1) which promotes macrophage infiltration. Obesity is a risk factor for type 2 diabetes and cardiovascular disease (CVD) (1-4). Several studies have shown that visceral obesity, in particular, is strongly associated with insulin resistance, hyperglycemia, dyslipidemia and hypertension. Subcutaneous fat deposition has also been associated with decreased risk of cardiovascular disease in some studies (5-9).
Recently, studies of germ-free mice focused attention on the intestine and its role in the etiology of obesity. Germ-free mice exhibited 42% lower fat mass than their conventionally raised littermates with a normal intestinal microbiota. These intestinal symbiotic bacteria can affect the regulation of energy metabolism by inducing formation of more capillaries to increase absorption, increasing monosaccharide uptake from bacterial breakdown of indigestible polysaccharides which stimulates triglyceride (TG) production and suppressing angiopoietin-like protein-4 which allows increased lipoprotein lipase activity leading to increased fat storage (67, 68, 70). Thus, the control of nutrient flux through the intestine may be the first line of defense against obesity and insulin resistance and their pathophysiological consequences.
To aid in the control of this bacterial “organ”, the intestine has developed secreted factors that are part of the innate immune system such as defensins, RELMb, and RegIII that prevent bacterial invasion of the intestinal mucosa, inflammation and increased intestinal permeability (71, 72). Intestinal inflammation, often caused by increased TNF-alpha, can cause intestinal insulin resistance resulting in overproduction of intestinal apolipoprotein B48 containing TG-rich particles (73). High fructose-induced intestinal insulin resistance also caused similar elevated TG flux across the intestine to create metabolic dyslipidemia (79). Although the intestine is not classically thought of as an insulin target tissue, many recent studies have utilized oral insulin to improve intestinal health, permeability and decrease plasma triglycerides and cholesterol (80). Oral insulin administration was shown to decrease atherosclerotic lesions in ApoE knockout mice (81).
In light of the divergent pathological nature of adipose tissue accumulation, it is of great interest to resolve the molecular differences between visceral and subcutaneous adipose tissue depots. Although anatomical location and vascularization are clearly different (10), the molecular basis of differences in metabolism and secretory profile between visceral (omental) and subcutaneous adipose tissues and their impact on whole body physiology are not completely understood. Indeed, understanding the life cycle of the adipocyte, tissue dynamics or fat depot-specific differences will involve gaining more insight into the complex stromal-vascular cell interactions and paracrine/endocrine environment in adipose tissue.
In the furtherance of such studies, two adipose-specific proteins have been identified. Initially, omentin 1 was shown to be a novel secreted factor that is detectable in human plasma and has human visceral fat depot-specific expression (86; 11-13; U.S. patent application Ser. No. 10/785,720 (U.S. patent application publication no. 2004/0220099)). Omentin 1 was named for its preferential expression in visceral (omental) rather than subcutaneous adipose tissue (11). Omentin 1 has been identified in other tissues at reduced expression levels and named intelectin (14), intestinal lactoferrin receptor (15) or endothelial lectin (16). It is expressed in intestinal Paneth cells (17), endothelial cells (16), as well as visceral adipose stromal-vascular cells (11). In vitro studies have shown that omentin increases insulin signal transduction by activating the protein kinase Akt/PKB, and enhancing insulin-stimulated glucose transport in isolated human adipocytes. Thus, omentin 1 may play a paracrine or endocrine role in modulating insulin sensitivity.
Omentin 2 has 83% amino acid identity with omentin 1 (16) and is also expressed preferentially in visceral fat although at much lower levels (87). Omentin 2 expression is highest in small intestine and lung but is not detected in the plasma (87). Preliminary studies (discussed herein) of omentin genetics indicate association of omentin 2 polymorphisms with metabolic syndrome traits and impaired glucose tolerance.
The two omentin genes, omentin 1 and omentin 2, are localized adjacent to each other in the 1q22-q23 chromosomal region (18) that has been previously associated with type 2 diabetes in several populations (19-23).
Another adipokine, visfatin/preB-cell colony enhancing factor, was reported to have visceral fat-specific expression and insulin-mimetic properties (83). However recent studies in humans have shown little difference between visfatin expression in visceral and subcutaneous adipose tissue depots, elevated visceral fat expression in obesity and no correlation with measures of insulin sensitivity (84, 85). Unlike the visfatin's insulin-mimetic properties, omentin was shown to augment insulin-stimulated glucose transport in 3T3-L1 adipocytes and isolated human adipocytes, thus, acting as an insulin-sensitizer (86). These data suggested that omentin secretion from visceral fat may positively impact insulin sensitivity and glucose homeostasis.
The evidence discussed above, and further presented herein, suggests a crucial relationship between the regulation of intestinal nutrient absorption and the metabolic responsiveness, endocrine function and development of adipose tissue. Strong genetic evidence points to omentin 2 as a metabolic syndrome susceptibility gene. It is critical to understand the role of omentin 2 in the intestine and its regulation. It is also equally important to understand the relationship between omentin 1 and 2. Both of these molecules have the potential to greatly impact visceral adipose metabolism and potentially affect whole body energy metabolism. Therefore, it is of great significance to determine the effect of obesity and inflammation on omentin expression so that an understanding of the role of these unique secreted factors in the dynamics of intestinal physiology, adipose biology, obesity and insulin resistance can be obtained. Furthermore, knowledge of the regulation of an omental fat-specific gene may offer insight into specifically targeting gene therapies to this depot, and will provide fundamental knowledge of ‘adipose depot-specific’ gene expression.
Obesity and subacute inflammation are associated with increased risk for development of chronic disease, including type 2 diabetes and cardiovascular disease (CVD). The prevalence of obesity among American men and women has increased dramatically in the past two decades. Thus, the obesity epidemic has major implications for health of the nation, and for predicted health care costs to society for treatment of chronic disease (76). Thus, further understanding of the mechanisms by which obesity alters or is altered by intestinal function, adipose tissue metabolism/endocrine function is a particularly important research priority. Understanding the mechanisms linking obesity and inflammation to altered adipose tissue, intestinal and whole body metabolism may lead to the development of therapeutic agents or interventions that can prevent the deleterious consequences of increased adiposity or to prevent the development of obesity per se.